The present invention relates generally to the treatment and prevention of hepatic fibrosis, and more particularly to the administration of pharmacologically active compounds for the treatment and prevention of viral hepatitis C.
The majority of patients suffering from chronic hepatitis are infected with either chronic hepatitis B virus (HBV), chronic hepatitis C virus (HCV) or autoimmune disease. While each type is associated with certain distinct characteristics, generally speaking, chronic hepatitis can progress to cirrhosis and hepatic failure. Unfortunately, there are few effective treatments for hepatitis. For example, treatment of autoimmune chronic hepatitis is generally limited to immunosuppressive treatment with corticosteroids. For the treatment of hepatitis B and C, the FDA has approved administration of recombinant interferon alpha. However,. interferon alpha is associated with a number of dose-dependent adverse effects, including thrombocytopenia, leukopenia, bacterial infections, and influenza-like symptoms. Indeed, normal interferon alpha dosing parameters for the treatment of chronic hepatitis B require discontinuance or dosing adjustment in approximately 20-50% of patients. Other agents used to treat chronic hepatitis B or C include the nucleoside analog ribovirin and ursodeoxycholic acid; however, neither has been shown to be very effective. [See Medicine, (D. C. Dale and D. D. Federman, eds.) (Scientific American, Inc., New York), 4:VIII:1-8 (1995)].
Indeed, current therapies do not effectively prevent or cure hepatitis C or the hepatic fibrosis associated with the disease. Clearly, new alternative treatment methods and agents are needed and would be welcomed by those plagued by hepatitis C who either cannot tolerate available treatment regimens or who are refractory to those regimens.
The present invention discloses the administration of vitamin E and other pharmacologically active compounds for the treatment and prevention of liver fibrosis associated with viral hepatitis C and other chronic liver diseases. Indeed, treatment with high doses of vitamin E may be effective in treating chronic hepatitis C in patients refractory to interferon.
The present invention also describes new methods for the treatment and prevention of hepatic fibrosis and hepatic conditions manifesting hepatic fibrosis involving the administration of compounds with antioxidant properties. In preferred embodiments, these new methods involve the administration of butylated hydroxytoluene and a metabolite of pentoxifylline, 1-[3-carboxypropyl]-3, 7-dimethylxanthine (metabolite 5 of pentoxifylline).
Specifically, the present invention contemplates a method of treating hepatitis C, comprising: a) providing i) a subject having symptoms of hepatitis C, and ii) an antioxidant; and b) administering a therapeutic amount-of the antioxidant to the subject under conditions such that the symptoms are diminished. In one embodiment, the subject is refractory to interferon. In some embodiments, the antioxidant is administered orally to the subject, whereas it is administered parenterally in other embodiments. In further embodiments, the antioxidant is d-xcex1-tocopherol. In some embodiments, the method further comprises the step prior to step b) of measuring the symptoms by liver biopsy; moreover, some embodiments of the method further comprise the step subsequent to step b) of measuring the symptoms by liver biopsy.
The present invention also contemplates a method of treating hepatitis C, comprising: a) providing i) a subject with hepatitis C having symptoms indicating fibrosis, and ii) d-xcex1-tocopherol; and b) administering a therapeutic amount of d-xcex1-tocopherol to the subject under conditions such that the symptoms are diminished. In particular embodiments, the subject is refractory to interferon. In certain embodiments, the d-xcex1-tocopherol is administered orally to the subject, while it is administered parenterally in other embodiments. When administered orally, the therapeutic amount of d-xcex1-tocopherol is from 800 units daily to 1600 units daily in preferred embodiments, and from 1000 units daily to 1400 units daily in more preferred embodiments. In some embodiments, the method further comprises the step prior to step b) of measuring the symptoms by liver biopsy. Moreover, some embodiments of the method further comprise the step subsequent to step b) of measuring the symptoms by liver biopsy.
As indicated above, the present invention also contemplates the administration of other antioxidants for the treatment of hepatic fibrosis. For example, the present invention contemplates a method of treating hepatic fibrosis, comprising: a) providing i) a subject with hepatic fibrosis, and ii) 1-[3-carboxypropyl]-3, 7-dimethylxanthine or butylated hydroxytoluene; and b) administering a therapeutic amount of 1-[3-carboxypropyl]-3, 7-dimethylxanthine or butylated hydroxytoluene to the subject under conditions such that the hepatic fibrosis is diminished. In particular embodiments, the 1-[3-carboxypropyl]-3, 7dimethylxanthine. or butylated hydroxytoluene is administered orally to the subject. When administered orally, the therapeutic amount of the 1-[3-carboxypropyl]-3, 7-dimethylxanthine is from 400 mg daily to 1200 mg daily in some embodiments. Other embodiments and aspects of the present invention will become apparent to those skilled in the art based upon the description that follows.
Furthermore, the present invention provides new methods for the treatment and prevention of hepatic fibrosis and hepatic conditions manifesting hepatic fibrosis involving the administration of 2,6-di-tert-butylphenols. Specifically, the present invention contemplates a method of treating hepatitis C, comprising: a) providing i) a subject having symptoms of hepatitis C, and ii) a 2,6-di-tert-butylphenol derivative; and b) administering a therapeutic amount of the 2,6-di-tert-butylphenol derivative to the subject under conditions such that the symptoms are diminished. In one embodiment, the subject is refractory to interferon. In some embodiments, the method further comprises the step prior to step b) of measuring the symptoms by liver biopsy; moreover, some embodiments of the method further comprise the step subsequent to step b) of measuring the symptoms by liver biopsy.
In one embodiment, the methods of the present invention involve the administration of a 2,6-di-tert-butylphenol selected from the group consisting of 4-propynoyl-2,6-di-tert-butylphenol, 4-(1xe2x80x2-hydroxy-2xe2x80x2-propynyl)-2,6-di-tert-butylphenol, 4-(3xe2x80x2-butynoyl)-2,6-di-tert-butylphenol, 4-butadienoyl-2,6-di-tert-butylphenol, 4-(4xe2x80x2-pentynoyl)-2,6-di-tert-butylphenol, 4-(4xe2x80x2-pentenoyl)-2,6-di-tert-butylphenol, 4-(2xe2x80x2-dimethoxymethyl-4xe2x80x2-pentynoyl)-2,6-di-tert-butylphenol, 4-(2xe2x80x2,2xe2x80x2-dimethyl-4xe2x80x2-pentynoyl)-2,6-di-tert-butylphenol, 4-(3xe2x80x2,3xe2x80x2-dimethyl4xe2x80x2-pentynoyl)-2,6-di-tert-butylphenol, 4-(4xe2x80x2-pentyn-3xe2x80x2one)-2,6-di-tert-butylphenol, 4-(5xe2x80x2-hexynoyl)-2,6-di-tert-butylphenol, 4-(5xe2x80x2-hexenoyl)-2,6-di-tert-butylphenol, 4-(2xe2x80x2-methyl-5xe2x80x2-hexynoyl)-2,6-di-ter-butylphenol, -4-(1xe2x80x2-hydroxy-5xe2x80x2-hexynyl)-2,6-di-tert-butylphenol, 4-(5xe2x80x2-hexynyl)-2,6-di-tert-butylphenol, 4-(1xe2x80x2-methylidine-5xe2x80x2-hexynyl)-2,6-di-tert-butylphenol, 4-[(S)-(xe2x88x92)-3xe2x80x2-methyl-5xe2x80x2-hexynoyl]-2,6-di-tert-butylphenol, 4[(R)-(+)-3xe2x80x2-methyl-5-hexynoyl)-2,6-di-tert-butylphenol, 4-(6xe2x80x2-heptynoyl)-2,6-di-tert-butylphenol, 4-(6xe2x80x2-heptyn-3xe2x80x2-one)-2,6-di-tert-butylphenol, 4-[4xe2x80x2-(2xe2x80x3-propynyl)-6xe2x80x2-heptyn-3xe2x80x2-one]-2,6-di-tert-butylphenol, 4-(7xe2x80x2-octynoyl)-2,6-di-tert-butylphenol, 4-[(E)-1xe2x80x2-penten4xe2x80x2-yn-3xe2x80x2-one)-2,6-di-tert-butylphenol, 4-[(E)-1xe2x80x2,6xe2x80x2-heptadiene-3xe2x80x2-one)2,6-di-tert-butylphenol, 4-(3xe2x80x2,3xe2x80x2-dimethoxypropionyl)-2,6-di-tert-butylphenol, 4-[2xe2x80x2-(1xe2x80x3,3xe2x80x3-dioxolane)acetyl]-2,6-di-tert-butylphenol, 4-(3xe2x80x2,3xe2x80x2-diethoxypropionyl)-2,6di-tert-butylphenol, 4-[2xe2x80x2-(1xe2x80x3,3xe2x80x3-oxathiolaneacetyl]-2,6-di-tert-butylphenol, 4-(2xe2x80x2,2xe2x80x2-dimethoxyethyl)-2,6-di-tert-butylphenol, 4-(5xe2x80x2,5xe2x80x2-dimethoxy-3xe2x80x2-pentanone)-2,6-di-tert-butylphenol, 4-(3xe2x80x2,3xe2x80x2-dimethyl-5xe2x80x2-hexynoyl)-2,6-di-tert-butylphenol, 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene]dihydro-2(3H)-furanone, N-methoxy-3(3,5-di-tert-butyl-4-hydroxybenzylidine)-pyrrolidin-2-one, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-thiazolidine, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-N-methylthiazolidine, R-830, CI-1004 and N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-aminobenzoic acid (i.e., xe2x80x9cR-840xe2x80x9d). In preferred embodiments, the methods of the present invention involve the administration of a 2,6-di-tert-butylphenol selected from the group consisting of 4-(5xe2x80x2-hexynoyl)-2,6-di-tert-butylphenol, 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-methylene]dihydro-2(3H)-furanone, N-methoxy-3-(3,5-di-tert-butyl-4-hydroxybenzylidine)-pyrrolidin-2-one, and R-840.
In another embodiment, the methods of the present invention involve the administration of a 2,6-di-tert-butylphenol of the general structure as shown in FIG. 9A, wherein R2 is xe2x80x94COxe2x80x94Xxe2x80x94CHRxe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94Xxe2x80x94CH2xe2x80x94CHRxe2x80x94, or COxe2x80x94NHxe2x80x94CX2xe2x80x94NHxe2x80x94, wherein R is hydrogen or a C1-C3 alkyl group, X is CH2 or oxygen, and X2 is oxygen or a sulfur. In particular embodiments, R2 is selected from the group consisting of xe2x80x94CO2CH(CH3)CH2xe2x80x94, xe2x80x94COCH2CH2CH2xe2x80x94, xe2x80x94CONHCONHxe2x80x94, and xe2x80x94CONHCSNHxe2x80x94.
In yet another embodiment, the methods of the present invention involve the administration of a 2,6di-tert-butylphenol of the general structure as shown in FIG. 10B, wherein X is hydrogen, xe2x80x94NH, xe2x80x94N(CH2)OH, xe2x80x94N-alkyl or xe2x80x94NNR1R2,
wherein the alkyl group is a C1-C6 alkyl,
R1 and R2 are each independently hydrogen or C1-C4 alkyl, and n is an integer from 0 to 3.
In some embodiments, the methods of the present invention involve the administration of a 2,6di-tert-butylphenol selected from the group consisting of 5-{[3,5-bis(1,1-dimethylethyl)4-hydroxyphenyl]methylene}-3-(3-methoxypropyl)-2-thioxo-4-thiazolidinone, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-3-[(2-ethylthio)ethyl]-4-thiazolidinone, 5-{[3,5-bis(1,1dimethylethyl)-4-hydroxyphenyl]methyl}-3-(3-methylthiomethyl)-4-thiazolidinone, 3-acetyl-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-thiazolidinone, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-3-[methyl(1-methylethyl)amino]-4-thiazolidinone, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-3-(methylsulfonyl)-4-thiazolidine, and 3-amino-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-thioxo-4-thiazolidinone.
In yet another embodiment, the methods of the present invention involve the administration of a 2,6-di-tert-butylphenol of the general structure as shown in FIG. 10C, wherein (1) X is sulfur, oxygen, NH or NCH3; (2) X1 is NH or NH3; and (3) Y and Y1 is oxygen or sulfur. In particular embodiments, the methods of the present invention involve the administration of 2,6-di-tert-butylphenol selected from the group consisting of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2,4-thiazolidinedione, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2,4-thiazolidinedione choline salt, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-(E)-2,4-thiazolidione, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-thioxo-4-oxazolidinone, 5-{[3,5-bis(1,1-dirmethylethyl)-4-hydroxyphenyl]methylene}-2,4-oxazolidinone, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-thioxo-4-imidazolidinone, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2,4-imidazolidinedione.
In another embodiment, the methods of the present invention involve the administration of a 2,6-di-tert-butylphenol of the general structure as shown in FIG. 10D, wherein (1) X is NH or N-lower alkyl; (2) R is hydrogen or methyl; and (3) Y is xe2x80x94SCH3, xe2x80x94SOCH3, xe2x80x94SO2CH3, xe2x80x94NHCN, xe2x80x94NH(Cxe2x95x90Z)NHR3, xe2x80x94NHNH(Cxe2x95x90S)NH2, xe2x80x94N(OR6)R4, xe2x80x94N(OH)COR, xe2x80x94NR4W, xe2x80x94(CH3)xe2x80x94CHxe2x80x94CO2R4, xe2x80x94(CH2)mCO2 R4, xe2x80x94S(CH2)nCO2R6 or xe2x80x94NR7COR6,
wherein Z is selected from the group consisting of oxygen, sulfur, NH and NCN,
W is CO2R7 and R7 is selected from the group consisting of xe2x80x94(CH3)xe2x80x94CHxe2x80x94CO2H, xe2x80x94(CH2)mCO2H, xe2x80x94(CH2)mOH, and xe2x80x94C(CH2OH)3,
n is 1 to 3; m is 1 to 5,
R3 is hydrogen, alkyl or aryl,
R4 is hydrogen or alkyl,
R5 is alkyl, aryl, or CF3,
R6 is hydrogen or alkyl, and
R7 is a lower alky.
In particular embodiments, the methods of the present invention involve the administration of 2,6-di-tert-butylphenol selected from the group consisting of (Z)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-imino-4-thiazolidinone methanesulfonate (1:1) salt, (Z)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-(methoxymethylamino)-4(5H)-thiazolone monohydrochloride, 2-oxime-(Z)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2,4-thiazolidinedione, (Z)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-(methylthio)-4(5H)-thiazolone, (Z)-5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-[hydroxy(1-methylethyl)amino]-(5H)-thiazolone, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4,5-dihydro-4-oxo-2-thiazolyl]cyanamide choline salt, 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-(methylthio)-4(5H)-oxazolone, 5-{[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]methylene}-4,5-dihydro-4-oxo-2-oxazolyl]cyanamide, and 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4,5-dihydro-1-methyl-4-oxo-1H-imidazol-2-yl-cyanamide.
In yet another embodiment, the methods of the present invention involve the administration of a 2,6di-tert-butylphenol of the general structure as shown in FIG. 11, wherein (1) R1 is hydrogen, lower alkyl, or xe2x80x94CONHR3, wherein R3 is hydrogen, lower alkyl, phenyl or substituted phenyl; and (2) R2 is hydrogen, lower alkyl, lower alkoxy, halogen, hydroxy, trifluoromethyl or CO2R4, wherein R is hydrogen, lower alkyl, phenyl or substituted phenyl. In particular embodiments, the methods of the present invention involve the administration of 2,6-di-tert-butylphenol selected from the group consisting of Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-1,3-dihydro-2H-indole-2-one; (Z)-3-{[3,5-bis( 1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-1,3-dihydro-5-methyl-2H-indole-2-one; (Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2,3-dihydro-2-oxo-1H-indol-1-carboxamide; (Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-1,3-dihydro-1-methyl-2H-indole-2-one; (Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-1,3-dihydro-7-methoxy-2H-indol-2-one; (Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2,3-dihydro-2-oxo-1H-indole-5-carboxylic acid ethyl ester; (Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-1,3-dihydro-7-methyl-2H-indole-2-one; (Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-1,3-dihydro-5-methoxy-1-methyl-2H-indole-2-one; (Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-4-chloro-1,3-dihydro-2H-indole-2-one; (Z)-3-{[3,5-bis(1,3-dimethylethyl)-4-hydroxyphenyl]methylene}-1,3-dihydro-4-methyl-2H-indole-2-one; (Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-1,3-dihydro-6-methyl-2H-indole-2-one; and (Z)-3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2,3-dihydro-2-oxo-1H-indole-5-carboxylic acid.
In yet another embodiment, the methods of the present invention involve the administration of a 2,6-di-tert-butylphenol of the general structure as shown in FIG. 12B, wherein (1) X is thio, sulfinyl or sulfonyl; (2) R is a lower alkyl selected from the group consisting of branched and straight chains; (3) R3 is hydrogen or lower alkyl; and (4) R4 is substituted or unsubstituted phenyl. In particular embodiments, the methods of the present invention involve the administration of 2,6-di-tert-butylphenol selected from the group consisting of 3-{[3,5-bis(1,1dimethylethyl)-4-hydroxyphenyl]thio}-N-(2,6-dimethylphenyl)propanamide, 3-{[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]-thio}-N-(2,6-diethylphenyl)propanamide, 3-{[3,5-bis(1,1-dimethylethyl)-4-hydroxy-phenyl]sulfinyl}-N-(2,6-dimethylphenyl)propanamide, 3-{[3,5-bis(1,1-dimethylethyl)-4hydroxyphenyl]sulfonyl}-N-(2,6-diethylphenyl)propanamide, 4-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio}butanoic acid, 4-{[3,5-bis(1,1-dimethyletfyl)-4-hydroxyphenyl]thio}-N-(2,6-dimethylphenyl)butanamide, 2-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio}pentanoic acid, 2-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio}-N-(2,6-dimethylphenyl)pentanamide, 2-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio}-N-(2,6-dimethylphenyl)acetamide, and 2-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio}-N-(2,6-dichlorophenyl)acetamide.
To facilitate understanding of the invention that follows, a number of terms and phrases are defined below.
The term xe2x80x9csubjectxe2x80x9d includes humans as well as other animals.
The term xe2x80x9chepatitis Cxe2x80x9d refers to subjects infected with the hepatitis C virus, a single-stranded RNA virus that possesses a lipid-containing envelope and is thought to be a member of the flavivirus family. The term encompasses all forms of hepatitis C, including acute hepatitis C and all forms of chronic hepatitis C (e.g., chronic active hepatitis and chronic persistent hepatitis).
The phrase xe2x80x9csymptoms of hepatitis Cxe2x80x9d refers broadly to clinical manifestations, laboratory and imaging results, as well as liver morphology and histology exhibited by subjects which suggest the presence of hepatitis C. Clinical manifestations may include, but are not limited to, abdominal pain, jaundice, hepatosplenomegaly, and ascites. Laboratory and imaging results may include, but are not limited to, elevated serum aminotransferase, bilirubin, and gamma-globulin levels, as well as an enlarged liver on computed tomography, magnetic resonance imaging, and hepatic ultrasonography. Hepatic morphological and histological indicators of hepatitis C may include, but are not limited to, deposition of fibrotic tissue evident through liver biopsy.
The phrases xe2x80x9csymptoms indicating fibrosis,xe2x80x9d xe2x80x9chepatic fibrosisxe2x80x9d and the like refer to hepatic morphological and histological indicators of fibrosis. Such indicators may include, but are not limited to, deposition of fibrotic tissue evident through liver biopsy and activation of the fibrogenesis cascade as evidenced by increased MDA-adducts, stellate cell activation, and enhanced expression of c-myb and collagen xcex11(I) mRNA in stellate cells.
The term xe2x80x9cdiminishedxe2x80x9d means that there has been a reduction in the extent of the symptoms of hepatitis C, hepatic fibrosis, etc. In general, such a reduction is demonstrated by objective indicators. For example, comparison of liver biopsy samples taken before and after administration of a therapeutic agent may indicate a reduction in fibrosis. In addition, reduction of symptoms may also be demonstrated by subjective indicators, such as a reduction in abdominal pain.
The term xe2x80x9coxidantxe2x80x9d refers to the electron acceptor in an oxidation-reduction reaction [i.e., the chemical reaction whereby electrons are removed (oxidation) from atoms of the substances being oxidized and transferred to those being reduced (reduction)]. The term xe2x80x9cantioxidantxe2x80x9d refers to compounds and combinations of compounds that prevent the process of oxidation, thereby preventing the effects of reactive oxygen species (e.g., free radicals) that may have adverse effects on a subject. For example, antioxidants may prevent oxidation of essential cellular constituents (e.g., ubiquinone) or prevent the formation of toxic oxidation products (e.g., peroxidation products formed from unsaturated fatty acids). In the context of the present invention, the determination of whether a compound has antioxidant properties (and therefore is an antioxidant) may include, but is not limited to, ascertaining whether the compound inhibits activation of the fibrogenesis cascade in the liver. As described in the Experimental section, such inhibition may he represented by a decrease in MDA-adducts and stellate cell activation, and decreased expression of c-myb and collagen xcex11(I) mRNA in stellate cells. Examples of compounds with antioxidant properties include vitamin E, beta carotene, propyl gallate, ascorbyl palmitate, and sodium bisulfite. Antiox(copyright) (Mayrand Pharmaceuticals, Greensboro, N.C.) is an antioxidant product that is commercially available over-the-counter; it contains beta carotene, vitamin C, and vitamin E. It should be noted that compounds that are antioxidants may also have other pharmacological functions.
The term xe2x80x9ctherapeutic compositionxe2x80x9d refers to a composition that includes a compound in a pharmaceutically acceptable form that prevents and/or reduces hepatic fibrosis. Generally speaking, the therapeutic compositions of the present invention contain a compound with antioxidant properties, and/or a 2,6-di-tert-butylphenol derivative. The characteristics of the form of the therapeutic composition will depend on a number of factors, including the mode of administration. For example, a composition for oral administration must be formulated such that the antioxidant compound and/or the 2,6-di-tert-butylphenol is pharmacologically active following absorption from the gastrointestinal tract. The therapeutic composition may contain diluents, adjuvants and excipients, among other things.
The term xe2x80x9cparenterallyxe2x80x9d refers to administration to a subject through some means other than through the gastrointestinal tract or the lungs. Common modes of parenteral administration include, but are not limited to, intravenous, intramuscular, and subcutaneous administration.
The terms xe2x80x9ctherapeutic amount,xe2x80x9d xe2x80x9ceffective amount,xe2x80x9d and the like refer to that amount of a compound or preparation that successfully prevents the symptoms of hepatic fibrosis and/or reduces the severity of symptoms. The effective amount of a therapeutic composition may depend on a number of factors, including the age, immune status, race, and sex of the subject and the severity of the fibrotic condition and other factors responsible for biologic variability.
The phrase xe2x80x9crefractory to interferonxe2x80x9d means that a treatment regimen involving the administration of interferon (e.g., interferon alpha) to a subject has had either no effect or a limited effect on the symptoms of hepatitis C. That is, interferon therapy may have alleviated some of the subject""s symptoms, but it did not alleviate all of the symptoms associated with hepatitis C viral infection or disease. In certain, but not all, cases, furter treatment with interferon is deemed to be medicinally unwarranted.
The term xe2x80x9cvitamin Exe2x80x9d is used synonymously with the term xe2x80x9cd-xcex1-tocopherol.xe2x80x9d Vitamin E activity is generally expressed in USP or International Units (IU), which are equivalent. One unit of vitamin E equals the biological activity of 1 mg of dl-xcex1-tocopherol acetate, 1.12 mg of dl-xcex1-tocopherol acid succinate, 910 xcexcg of dl-xcex1-tocopherol, 735 xcexcg of d-xcex1-tocopherol acetate, 830 xcexcg of d-xcex1-tocopherol acid succinate,; and 670 xcexcg of d-xcex1-tocopherol.
The term xe2x80x9c2,6-di-tert-butylphenol derivativesxe2x80x9d encompasses compounds having a phenol substituted with two tertiary butyl substituents at the 2 and 6 positions of the phenol ring. Examples of 2,6-di-tert-butylphenol derivatives for use in the methods of the present invention include, but are not limited to compounds having the general structure as shown in FIGS. 8-12.
The terms xe2x80x9clower alkylxe2x80x9d refers to straight or branched chain alkyl groups having from 1 to 6 carbon atoms (i.e., methyl, ethyl, propyl, butyl, pentyl, or hexyl, and isomers thereof). As used herein, the term xe2x80x9calkylxe2x80x9d refers to a straight or branched hydrocarbon group having the formula CnH2m+1, wherein C and H refer to carbon and hydrogen atoms, respectively, and n is an integer xe2x89xa71.
The term xe2x80x9carylxe2x80x9d refers to an unsubstituted phenyl, or a phenyl having one or more substituents selected from the group consisting of amino, halo, hydroxy, lower alkyl, lower alkylaminoalkyl, lower dialkylaminoalkyl, trifluoromethyl, lower alkoxy, and the like.
The term xe2x80x9chalogenxe2x80x9d refers to the halogen elements, which includes fluorine, chlorine, bromine and iodine. The term xe2x80x9chalogen-containing compoundsxe2x80x9d refers to compounds comprising a halogen functionality (i.e., fluoro, chloro, bromo and iodo groups).
The terms xe2x80x9cR-830,xe2x80x9d xe2x80x9cR-840,xe2x80x9d and xe2x80x9cCI-1004xe2x80x9d are 2,6-di-tert-butylphenol compounds with chemical structures as shown in FIG. 12.